1. Field of the Invention
The invention relates to certain novel benzenesulfonic acid addition salts of 1,1-dioxopenicillanoyloxymethyl 6-[D-(2-amino-2-phenylacetamido)]penicillanate (sultamicillin) having advantages for use in antibacterial formulations.
2. Description of the Prior Art
Barth, in U.S. Pat. No. 4,234,579 issued Nov. 18, 1980, discloses penicillanic acid 1,1-dioxide (sulbactam) and esters thereof which are readily hydrolyzable in vivo, useful as antibacterial agents and for enhancing the effectiveness of beta-lactam antibiotics, such as ampicillin, against many beta-lactamase producing bacteria.
Bigham, in U.S. Pat. No. 4,244,951 issued Jan. 13, 1981; and Netherland Patent Application No. 8,000,775 published Aug. 15, 1980, corresponding to British Patent Application No. 2,044,255 both disclose novel conjugates of penicillanic acid 1,1-dioxide with known penicillin antibiotics which are linked via a methylenedioxy group. These conjugates are of the general formula ##STR2## wherein R.sup.b is the acyl group of a natural or semisynthetic penicillin.
The compound of the above formula wherein R.sup.b is D-(2-amino-2-phenylacetyl) is designated herein as "sultamicillin" and will be referred to herein by that name. It is a methylenedioxy linked conjugate of penicillanic acid 1,1-dioxide and ampicillin.
Sultamicillin free base has been found to have poor handling characteristics and inadequate stability. The only salt of sultamicillin specifically disclosed in the art is the hydrochloride. While it is suitable for certain antibacterial formulations, it also has poor solid state stability, which is reflected in handling difficulties, and is highly soluble in water in which it is subject to hydrolytic decomposition. Thus, it is unsuitable for aqueous dosage formulations, including the aqueous suspensions preferred in pediatric medicine.
Crystalline forms of compounds are ordinarily preferable to the non-crystalline forms thereof. The crystalline materials have superior stability, appearance and handling characteristics when compared to their amorphous counterparts. For pharmaceutical use crystalline compounds are especially advantageous in manufacturing procedures and in formation and use of acceptable dosage forms such as solutions, suspensions, elixirs, tablets, capsules and various pharmaceutically elegant preparations required by the medical and pharmaceutical professions.
For pediatric administration it is well recognized by those of skill in the art that solutions or liquid suspensions are highly preferable dosage forms. Tablets and capsules are difficult for children to swallow and the amount of drug delivered is not as flexible as is often required for pediatric drugs. With liquid dosage forms, by contrast, the amount of drug delivered to the patient can be varied over a wide range merely by regulating the volume of dose of known concentrations.
Conjugate antibiotics such as sultamicillin are susceptible to partial hydrolysis to its components (ampicillin and sulbactam) upon storage in aqueous media. Thus, the enhanced stability in aqueous suspensions of a salt of sultamicillin of limited solubility, relative to another salt of significantly higher solubility, such as the hydrochloride, is evident.